Interstitial cystitis (1C) and Irritable bowel syndrome (IBS) affect 15-30% of the US population, invariably women, and are characterized by overlapping symptoms of chronic pelvic pain, urinary and bowel dysfunction. Their pathophysiology is poorly understood. They impair quality of life and impose major health care burden. Most patients are dissatisfied with current therapies. IBS &1C therapy fail because they do not remedy the underlying problem. Our goal is to investigate the neurobiologic mechanisms that cause 1C and IBS. Our preliminary studies in IBS reveal maladaptive neuroplastic changes within the central and peripheral nervous system, but the pelvic floor-brain neuromuscular axis in IC/IBS patients has not been examined. We hypothesize that bidirectional signaling in the brain-pelvic floor/gut axis is deranged in IC/IBS patients. We will test this by using a new, noninvasive and validated method of studying the brain-pelvic floor axis. We propose four specific aims: 1) Examine the hyperexcitability of the afferent-pelvic floor-brain axis in 66 patients with 1C, 66 patients with 1C and IBS and 30 healthy controls by measuring the cortical evoked potentials (CEP) and sensory thresholds after electrical stimulation of the rectum and anus. 2) Study the efferent brain-pelvic floor axis by stimulating the cortex with transcranial magnetic stimulation and record the anal and rectal motor evoked potentials (MEP). 3) Determine the locus for neuronal modulation i.e are the neuroenteric changes due to central or peripheral neuronal sensitization or both, by evoking anal and rectal MEPs after selectively stimulating the lumbar and sacral nerves bilaterally, and by comparing segmental with transcranial-induced MEPs. 4) Evaluate why IC/IBS patients experience bowel symptoms by assessing anorectal sensation and sensori-motor function and correlating bowel and bladder symptoms with anorectal hypersensitivity, rectal compliance and pelvic floor dysfunction. Our multidisciplinary, comprehensive approach will investigate the neurobiologic mechanisms of chronic pelvic pain in IC/IBS, and how they differ from 1C. Our studies will provide novel mechanistic insights regarding the pathobiology of these overlapping pain syndromes, which could have a significant impact on our understanding of 1C/IBS, and pave the way for mechanistic-based therapies.